COVID-19 Open Structures

Contents

Background

The COVID-19 crisis is bringing out the best in the communities we belong to, with many people giving deep thought to how we can use our skills to help. Structural biologists have much to offer in the longer-term resolution of the crisis, by providing a molecular-level understanding that can inform the development of new therapies such as drugs or vaccines, as well as a deeper understanding of the biology of the virus and its pathogenic mechanisms.

COVID-19 Open Structures
has been set up to coordinate an open science initiative to accelerate progress in this structural understanding of COVID-19. Taking a completely open science approach will ensure that there are no unnecessary delays in the determination of structures related to COVID-19, whether they're from the SARS-CoV-2 virus, interacting host proteins, or complexes. When determining a structure turns out to be difficult, help can come from people with specialised skills in your own field or with other areas of expertise, such as molecular modelling or another method for structure determination.

Modelling

The CASP (Critical Assessment of Structure Prediction) organisers have launched an initiative to mobilise the structure prediction community to predict and refine 3D structures of COVID-19-related proteins and relevant complexes that either have unknown structure or are non-trivial modelling targets, described at the
CASP Commons
site. Note that the models are being refined iteratively and much more extensively than typically done in a normal CASP round, which should make them even better than the impressive results seen in recent years. The CASP initiative has been taken up with great enthusiasm by the prediction community.

The related CAPRI (Critical Assessment of PRedicted Interactions) community is offering to help in predicting the 3D structures and interaction interfaces of protein complexes and large assemblies (homo- or hetero-complexes), starting from predicted structures of the individual components or structures determined
experimentally by X-ray diffraction or cryo-EM (see the
CAPRI site
). The community has also developed a wide range of tools,
for analysing potential binding interfaces and identifying biologically meaningful association modes.

X-ray crystallography

Solving the phase problem can still be a real bottleneck, when there are no good molecular replacement models and no good sources of experimental phasing. An open science approach will help to escape these bottlenecks in a number of ways. Structure prediction has reached a level of maturity where predicted ab initio models and distant homology models can be accurate enough to solve new structures by molecular replacement. Experts in data analysis may well be able to improve the quality and resolution of diffraction data, starting from the same raw images. Similarly, experts in phasing may have tricks or advanced algorithms allowing them to solve the phase problem from data that were insufficient for routine structure solution. On a number of occasions at crystallographic computing schools and workshops, we have seen extremely difficult structures yield to the combined expertise of a number of developers and "power users" of the software, none of whom knew how to solve every problem that arose.

Cryo-EM

In spite of the fantastic "resolution revolution" in cryo-EM, some samples are still recalcitrant and fail to yield high-resolution reconstructions. These reconstructions can still be of great value if shared openly with the rest of the scientific community. For instance, reconstructions at 5-10 Å resolution have been used successfully by crystallographers to obtain initial phases for crystals that diffract to higher resolution, allowing bootstrapping to a final atomic model. Such reconstructions could also benefit from interaction with the modelling community: predicted structures could be docked into a reconstruction, providing biological insight into complexes, and structure prediction could be improved by being informed by the constraint of fitting into a reconstruction.

COVID-19 Open Structures platform

Microsoft Teams has been chosen as the platform to coordinate the effort. It was chosen because it is available, it possesses a sufficient set of features, and we have some familiarity with it. A new Team,
UOC_Covid-19 Open Structures
, has been established, and the site is ready for new targets. For each new target, a new channel will be created to share insights and results as they emerge.

If you believe that you can bring expertise to this initiative and you're willing to share your insights and any promising results immediately with others, please get in touch and we'll add you to the team. Send an email to
Randy Read
and to
Massimo Sammito
, and you should receive an email with a link that will allow you to join the Team and download the desktop app (which is probably better than the web interface). If you already have a Microsoft account or a Skype account associated with a particular email address, use that address in your request. If not, you will be required to set up a (free) Microsoft account before joining the Team.

If you have diffraction data involving a SARS-CoV-2 protein, a host protein relevant to pathogenesis, or a complex, but you are not immediately able to solve the structure, contact the
CASP organisers
with the sequence(s) of the construct(s) that went into the crystallisation drop. If relevant predictions have already been made, any unreleased models will be released at this point (along with predictions of local accuracy) so they can be used in molecular replacement trials. If proteins in your crystals are not already modelling targets, the CASP organisers will consider them as potential new targets for the modelling community. At the same time, email
Randy Read
and
Massimo Sammito
with the information about what was crystallised, including stoichiometry if known, and with diffraction data (in the form of intensities) or information on how to access it. We will add you to the Team, create a new target channel, upload the target data, links and other information, and send an alert to everyone who has registered. It would be ideal also to provide a DOI or URL pointing at the raw images for the diffraction data. Data from different crystal forms or poorly isomorphous crystals can also be incredibly valuable. If you need advice on uploading data, Graeme Winter has provided useful documentation on the Teams site.

If you have cryo-EM data on a relevant molecule or complex (particularly at a resolution that does not allow building an atomic model with confidence), please consider joining this initiative and making your data open. You are encouraged to contact the
CASP organisers
, who could then consider releasing your structure as a data-assisted modelling challenge to the CASP community.

Publication policy

The most important thing in the current circumstances is to make relevant structural information available as quickly as possible. Eventually, of course, structures that are solved with the participation of people in this open science initiative will be published. It seems sensible to expect that the group that provided the project and the original experimental data would lead any publication, but also that anyone who made an important contribution would be appropriately recognised, most likely as one of the authors. In the spirit of this initiative, it would be great if any manuscripts arising would be made accessible immediately through a preprint server such as bioRxiv.